Pam Harrison

September 04, 2015

AMSTERDAM — A pharmacogenomic test that measures DNA variations in genes involved in drug metabolism and response has been shown to predict individual patient response to psychotropic medications and enhance treatment outcomes compared with treatment as usual, new research shows.

The study was presented here during the 28th European College of Neuropsychopharmacology (ECNP) Congress.

"Most clinicians in this field know that it is very challenging to treat patients with depression or anxiety because the drugs we have only initially work for about 50% of patients, and success goes down with each successive drug failure," Anthony Altar, PhD, senior vice president, Assurex Health, maker of the test that sponsored the study, told Medscape Medical News.

"So we are focusing on patients who do not have a good response to their current drug, and we are finding that patients do much better when their healthcare provider is aided by the GeneSight test results," he said.

The GeneSight Psychotropic test involves six genes that encode for the cytochrome P450 (CYP) enzymes that metabolize most drugs, including those used to treat depression and anxiety.

As Dr Altar explained, some variations in the genes that produce CYP450 enzymes decrease or abolish a patient's ability to metabolize drugs, resulting in higher drug levels in the blood and subsequently higher drug levels in the brain, causing undue side effects.

Conversely, patients who metabolize drugs very quickly end up with lower levels of drug in the blood and lower levels of drug in the brain, decreasing efficacy.

Because most brain-active drugs are metabolized by multiple CYPs, it is important to measure multiple genes that encode for different CYP enzymes to best predict the altered metabolism of each medication, researchers note.

The GeneSight Psychotropic test uses this combinatorial pharmacogenomic approach and includes two additional genes, one that encodes a serotonin response protein in the brain, and one that encodes the serotonin transporter that selective serotonin reuptake inhibitors block.

To obtain test results, physicians take a cheek swab from their patient and send it to Assurex Health, where it is analyzed for DNA variations.

Results of the analysis are detailed in a report, and psychotropic medications are placed into one of three categories: use as directed; use with caution; or use with increased caution and with more frequent monitoring.

Each of these categories are color-coded as green, yellow, and red, respectively; footnotes for drugs in the yellow and red categories contain recommendations for potential dose adjustments.

In three prospective clinical trials, patients who had a suboptimal response to their current medication or who were experiencing side effects were randomly assigned either to a guided group, where clinicians received a GeneSight report within 1.5 days of sending in their patients' DNA, or to a treatment-as-usual group, in which there was no guidance.

Treatment response to medication was monitored using the 17-item Hamilton Rating Scale for Depression (HAM-D17) during the next 8 to 10 weeks.

In a pooled analysis of the three studies, patients in the unguided group who had been treated with a "red category" medication showed only a modest 10% improvement on the HAM-D17 scale during the study period.

Overall, the unguided group improved by 23%, which is a typical response for antidepressants.

In contrast, the GeneSight-guided group had achieved a significantly greater 40% overall improvement in the HAM-D17 scores at study end point.

"We found that the odds of a patient having a response to treatment — defined as a 50% decrease in the HAM-D17 by study end point — was 2.3 times greater for patients whose clinicians were guided by the test compared to those who received treatment as usual," Dr Altar reported.

Comparison Study

In a comparison of their combinatorial pharmacogenomics approach to single-gene analyses (reported in an article in Molecular Neuropsychiatry that is currently in press), Dr Altar and colleagues analyzed outcomes for patients who were prescribed baseline medications metabolized by, or which acted through, each of the genes represented in the GeneSight test.

Test results significantly predicted poorer depression outcomes and a higher degree of healthcare utilization for patients prescribed red category medications.

In contrast, single gene analysis was unable to predict almost all health outcomes with the exception of one CYP phenotype.

"If a drug is metabolized by multiple CYPs and depends on response proteins in the brain for its mechanism of action, then one shouldn't expect to predict a patient's response by using just one gene at a time, and that's exactly what we saw," Dr Altar observed.

Assurex Health recently completed another study (Cur Med Res Opin. 2015;July 23:1-11) in which test results were provided to more than 2000 depressed patients and their clinicians.

Health utilization in the guided group was compared with that of more than 10,000 similar, demographically matched patients whose treatment was not guided by test results.

"An annual savings of over $1000 on prescription medications was realized for patients who received the GeneSight test," Dr Altar noted.

"And when physicians made changes that were congruent with test results — they either moved patients off red category drugs or they adjusted the dose in accordance with our recommendations — cost savings were over $2700 a year for those patients," he said. "The rapidity, the simplicity, and the accuracy of the test are of real value to physicians."

The GeneSight Psychotropic test is now reimbursed by Medicare.

Asked to comment on the value of the test, session co-chair Shitij Kapur, MD, dean, Institute of Psychiatry, and professor of schizophrenia, imaging, and therapeutics, King's College London, United Kingdom, told Medscape Medical News that although a number of exciting genetic findings have been reported to date, few have translated to the clinic.

"This test is one of the first commercially available genetic tests which is beginning to show evidence of clinical utility in psychiatry," Dr Kapur said in written correspondence.

"And while tests such as this don't deterministically predict outcome, they do increase the likelihood of better results," he said, adding that he expects that it will be exciting to see how tests such as this one demonstrate their utility in practice and find their place in formal guidelines and algorithms.

Dr Altar is senior vice president at Assurex Health. Dr Kapur has disclosed no relevant financial relationships.

28th European College of Neuropsychopharmacology (ECNP) Congress. Abstract S.02.03 Presented August 29, 2015.

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